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The glucocorticoid receptor (GR) is a member of the nuclear receptor superfamily, which controls programs regulating cell proliferation, differentiation, and apoptosis. We have identified an unexpected role for GR in mitosis. We discovered that specifically modified GR species accumulate at the mitotic spindle during mitosis in a distribution that overlaps with Aurora kinases. We found that Aurora A was required to mediate mitosis-driven GR phosphorylation, but not recruitment of GR to the spindle. GR was necessary for mitotic progression, with increased time to complete mitosis, frequency of mitotic aberrations, and death in mitosis observed following GR knockdown. Complementation studies revealed an essential role for the GR ligand-binding domain, but no clear requirement for ligand binding in regulating chromosome segregation. The GR N-terminal domain, and specifically phosphosites S203 and S211, were not required. Reduced GR expression results in a cell cycle phenotype, with isolated cells from mouse and human subjects showing changes in chromosome content over prolonged passage. Furthermore, GR haploinsufficient mice have an increased incidence of tumor formation, and, strikingly, these tumors are further depleted for GR, implying additional GR loss as a consequence of cell transformation. We identified reduced GR expression in a panel of human liver, lung, prostate, colon, and breast cancers. We therefore reveal an unexpected role for the GR in promoting accurate chromosome segregation during mitosis, which is causally linked to tumorigenesis, making GR an authentic tumor suppressor gene.

Original publication

DOI

10.1073/pnas.1411356112

Type

Journal article

Journal

Proc Natl Acad Sci U S A

Publication Date

28/04/2015

Volume

112

Pages

5479 - 5484

Keywords

DNA damage, aneuploidy, cancer, glucocorticoid receptor, mitosis, Animals, Cell Transformation, Neoplastic, Chromosome Segregation, Gene Expression Regulation, Neoplastic, Humans, Mice, Mice, Mutant Strains, Mitosis, Neoplasms, Protein Structure, Tertiary, Receptors, Glucocorticoid, Tumor Cells, Cultured, Tumor Suppressor Proteins